关键词: 抗乳腺癌, 帕博西尼, 合成

Abstract: Palbociclib, a new drug for treating metastatic breast cancer, was approved by the FDA in 2015. Nine synthesis routes of palbociclib were reviewed in this paper. The comparison and analysis of these synthesis routes showed that the synthesis of palbociclib had four key steps:constructing pyrimidinopyridone, introduction of 5-piperazin-1-yl-pyridin-2-ylamino in 2-position, acetyl in 6-position, and cyclohexyl in 8-position. Traditional synthesis routes have many disadvantages, such as too many reaction steps, used expensive metal palladium, toxic organotin compounds and LiHMDS, severe reaction conditions required, and low gross yields. The newly-developed synthesis routes improved the synthesis process of palbociclib through selecting proper raw materials and reactions. Newly developed reactors (like microwave-ultrasonic reactors)or one-pot routes reduced the reaction steps and avoided using palladium and organotin compounds so that the synthesis routes resulted in few reaction steps, high yields, environment-friendliness, and asset of industrialization. The synthesis routes of palbociclib are continuously improved by using cheap and readily available raw materials and environmentally benign agents, reducing synthesis steps, simplifying operation, having gentle reaction conditions and high total yields. Among the reported synthesis routes, the route 8 showed the potential of commercialization if LiHMDS can be replaced by a catalyst with simple operation. The route 6 has the greatest potential for industrialization if the scale-up of microwave-ultrasonic reactors can be solved. Besides, the synthesis method of deuterated palbociclib, which has better pharmacokinetics property and higher stability in vivo, is also introduced, and can be further improved according to the advanced synthesis routes of palbociclib.

Key words: anti-breast cancer drug, palbociclib, synthesis